Certain imidazo(1,2-b)-1,2,4-thiadiazole compounds

ABSTRACT

Novel 2-substituted-1,2,4-thiadiazolo-(2,3-a)-imidazoles of the formula   AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF; AND PROCESS FOR THEIR PREPARATION. These 2-substituted-1,2,4-thiadiazolo(2,3-a)-imidazoles are useful as fungistatic and fungicidal agents.

United States Patent [1 1 Beards,

[111 3,901,903 [451 Aug. 26, 1975 CERTAIN IMIDAZO[l,2-B]-l,2',4-THIADIAZOLE COMPOUNDS 75 Inventor: Colin C.Beard, PaloAlto, Calif.

73 Assignee: Syntelk (U. S.A.)"Inc., Palo Alto,

Calif.

22 Filed: on. 4, 1973 21 Appl. No.: 403,473

[52] U.S. Cl...26.0/306.8F 260/250 BN; 260/256.5 R; 260/294.8 C;260/309; 424/200; 424/232; 424/250; 424/251; 424/263; 424/270 PrimaryExaminer-Richard J. Gallagher Attorney, Agent, or Firm-Gerard A.Blaufarb; William B. Walker ABSTRACT Novel 2 -substituted- 1 ,2,4-thiadiazolo-[ 2,3-a] imidazoles of the formula S N I E N and thepharmaceutically acceptable salts thereof; and process for theirpreparation. These 2-substitutedl,2,4-thiadiazolo-[2,3-a1-imida2oles areuseful as fungistatic and fungicidal agents.

' 15 Claims, No Drawings CERTAIN mmAzof1.,2 B1 i;2,4 T HlADlAz0LE U PS a.This invention relates. to novel 2-subs tituted-1,2,4-

R is hydrogen or lower alkyl; and the pharmaceutically acceptable saltsthereof, and processes for the preparation thereof. v.

thiadiazolo-[2,3-a]-imi 1azo le compounds of' the for- 5 mula:

wherein .R is" J wherein R and R are e'ach hydrogen, lower alkoxy,

halo, nitro, lower alkyl,'lower alk-ylthio, lower alkylsulkyl; and r ,ri

The terms lower alkoxy, lower alkyl, lower alkylthio, and loweralkylsulfinyl as used above and in the claims 'are inclusive of moietiescontaining from 1 to 4 carbon 7 atoms, for example, methyl,ethyl,propyl, isopropyl,

butyl and tertf-butyl I The term halo as used above and in theclaims isinclusive of chl'oro, bromo, fluoro and iodo.

The compounds of Formula I are chemotherapeutic "agents which possessfungistatic and fungicidal properties and thus are useful in combattingfungus infections.

Amongst the fungi against which the compounds of Formula I exhibitfungistatic and fungicidal activity are:

l R and N 1 7 'M. andounini V H. gramineum Cr. neoformans R. solani'.='A.'solani T tonsurans T. schoenleinii 3 4 Particularly preferred arethose compounds, of 'Forsubstituted-l,2,4-Ihiadiazolo+[ 2,3-a]rimidazole.hydromula I wherein R is phenyl, 4-chlorophenyl, 4- chlorides, whichupon treatment with a base, e.g., ammethoxyphenyl, 4-methylphenyl,-4-methylthiophenyl, monia, sodium or potassium carbonate yield thecorre- 4-methylsufinylphenyl, 4-tert.-butylphenyl, 4-trisponding freebasessThe free base compounds of Forfluoromethylphenyl, 2-furyl,3-furyl, Z-naphthyl, 2- mula-I are,.i f desired; converted to theirpharmaceutithienyl, 3-thienyl, Z-thiazolyl, 4'-thiazolyl, 5-thiazolyl,cally acceptable salts by reaction with pharmaceuti-2-methyl-4.-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- callyacceptable acids, such as those set forth below, pyrazinyl,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, according to methodsknown to those skilled in the art. 1,2,3-thiadiazolyl, and1,2,5-thiadiazolyl. Alternatively,- other oxidizing agents, e.g., m- Thecompounds of Formula I are prepared according chloroperbenzoic acid,bromine, chlorine, peracetic to the following generalized reactionscheme: acid, hydrogen peroxide, and the like, can be used in H H N g; VNH CR [2 2 2 II r III R i 5 H H N i l N 4 E NH CR v t N I Iv V I whereinR is defined as above. I place of sulfuryl chloride, at a temperature offrom The carbonylamino compounds of Formula II] are about 40 to 40C.,for from about A. to 6 hours, in an obtained by treating the2-aminoimidazole of Formula inert organic solvent, e.g., chloroform, andthe like, to

II, preferably as its hydrochloride, hydrobromide, or treat thecompounds of Formula IV. When the reaction sulfate salt, with an acidchloride (RCOCl), acid ester is carried out using bromine or chlorine itis preferred (RCOOR wherein R is methyl or ethyl), or the mixed that thetemperature be between about 0 and 30C. In

anhydride of a free acid (RCOOH) and trifluoroacetic addition, 'When theoxidation reaction is carried out id, using bromine or chlorine, thecompounds of Formula The reaction of the compounds of Formula II with anI can, if desired, be isolated as their pharmaceutically acid chloride(RCOCl) to obtain the carbonylamino acceptable hydrobromide orhydrochloride salts, or compounds of Formula III is carried out in thepresence treated with a base, e.g., ammonia, sodium or potasof anorganic solvent, e.g., pyridine, acetone, tetrahysium bicarbonate andthe like, to obtain the corredrofuran, and the like, at a temperature offrom about spending free bases. -40 to 35C. for from about 2 to 20hours. 7 When the oxidation reaction is carried out using The reactionof the compound of Formula II with an other than sulfuryl chloride,bromine or chlorine, the acid ester (RCOOR to obtain the carbonylaminothus-obtained free bases of Formula I can be converted compounds ofFormula III is carried out at a temperato their pharmaceuticallyacceptable salts by reaction ture of from about 100 to 200C. for fromabout 1 to with pharmaceutically acceptable acids, for example, 20hours. inorganic acids, e.g., halogen hydroacids (particularly Thereaction of the compound of Formula II with a hydrochloric andhydrobromic), nitric acid, phosmixed anhydride of a free acid (RCOOI-I)and trifluophoric acids, sulphonic acids, monoand dicarboxylic roaceticacid, prepared from the free acid and trifluoacids, and the like; andorganic acids, e.g., acetic, maroacetic acid anhydride, to Obtain thcarbonylamino leic, succinic, tartaric, lactic, citric, sorbic,salicylic, compounds of Formula III is carried out in the presence d thlik of an inert organic solvent, e.g., tetrahydrofuran, ace- Thcompounds f F 1 1 or h h itone, and the like, and in th pr s of a base,gq cally acceptable saltsthereof, can be formulated into triethylamine,and the like, at a temp ra ur of fr solutions, creams and ointments,according to methods about 20 to 30C. for from a out 1 0 20 hOufS- knownto those skilled in the art, for topical administra- The thus-obtainedcarbonylamino compounds of tion. Preferably a concentration of fromabout 0.5 to 5 Formula III, obtained by reaction with an acid chloride,percent of the active ingredient is used. acid ester, or mixedanhydride, as described above, are It is understood that isolation ofthe compounds dethen converted to the corresponding thionylcarscribedherein can be effected by any suitable separabonylaminocompounds ofFormula IV by treatment tion or purification procedure, such as, forexample, with phosphorous pentasulfide (P 8 in an inert orextraction,filtration, evaporation, distillation, crystalliganic solvent, e.g.,pyridine, dioxane, and the like, at a zation, thin-layer chromatographyor column chromatemperature of from about to C., for from tography, or acombination of these procedures. Illusabout 1 to 20 hours. trations ofsuitable separation and isolation procedures The 2-substitutedl,2,4-thiadiazolo-[2,3-a]- can be had by reference to the-"examplesdescribed imidazole compounds of Formula I are obtained by herein below/However, other equivalenfseparation or treating the compounds of FormulaIV with sulfuryl isolation procedures could, of course, also'be used.chloride, in an inert organic solvent, e.g., chloroform, A furtherunderstanding of the invention can be had methylene chloride, and thelike, at a temperature of I from the following non-limiting examples.Also, where from about 0 to 50C., preferably 15 to 25C., for necessary,examples are repeated to provide starting from about 5 minutes to 6hours, to obtain the 2- materials for subsequent examples.

EXAMPLE 1 A. To a suspension of 6.8 g. of 2-aminoimidazole hydrochloridein 100 ml. of pyridine at --",C. there is added 6.8 ml. of benzoylchloride. The thus-obtained reaction mixture is allowed to warm slowlyto between 2030C. (room temperature), and maintained at this temperaturefor 12 hours, diluted with water and filtered to give a residue which isrecrystallized from methanol to yield 2-phenylcarbonylaminoimidazole[(Ill), R=phenyl].

Similarly, substituting a stoichiometric equivalent amount of4-chlorobenzoyl chloride,

4-methoxybenzoyl chloride,

4-methylbenzoyl chloride,

4-methylthiobenzoyl chloride,

4-methylsulfinylbenzoyl chloride,

4-tert.-butylbenzoyl chloride, 4-trifluoromethylbenzoyl chloride,

2-furoyl chloride,

3-furoyl chloride,

Z-naphthoyl chloride,

2-thenoyl chloride,

3-thenoyl chloride,

Z-thiazoloyl chloride,

4-thiazoloyl chloride S-thiazoloyl chloride,

2-methyl-4-thiazoloyl chloride,

Z-pyridinoyl chloride,

3-pyridinoyl chloride,

4-pyridinoyl chloride,

2-pyrazinoyl chloride,

3-isothiazolyl chloride,

4-isothiazolyl chloride,

S-isothiazolyl chloride,

l,2,3-thiadiazol-4-oyl chloride, and

1,2,5-thiadiazol-3-oyl chloride, for 3-benzoyl chloride in the procedureof Example 1A, is productive of2-(4-chlorophenylcarbonylamino)-imidazole,2-(4-methoxyphenylcarbonylamino)-imidazole,2-(4-methylphenylcarbonylamino)-imida2ole,2-(4-methylthiophenylcarbonylamino)-imidazole,2-(4-methylsulfinylphenylcarbonylamino)- imidazole, I2-(4-tert.-butylphenylcarbonylamino)-imidazole,

2-( 4-trifluoromethylphenylcarbonylamino imidazole,

2-(2-furylcarbonylamino)-imidazole,

2-( 3-furylcarbonylamino )-imidazole,

2-(Z-naphthylcarbonylamino)-imidazole,

2-( 2-thienylcarbonylamino )-imidazole,

2-( 3-thienylcarbonylamino )-imidazole,

2-( 2-thiazolylcarbonylamino )-imidazole,

2-(4-thiazolylcarbonylamino)-imidazole,

2-(S-thiazolylcarbonylamino)-imidazole,

2-( 2-methyl-4-thiazolylcarbonylamino)-imidazole 2-(2-pyridylcarbonylamino)-imidazole,

2-( 3-pyridylcarbonylamino )-imidazole,

2-(4-pyridylcarbonylamino)-imidazole,

2-(Z-pyrazinylcarbonylamino)-imidazole,

2-( 3-isothiazolylcarbonylamino )-imidazole,

2- (4-isothiazolylcarbonylamino)-imidazole,

2-( 5-isothiazolylcarbonylamino )-imidazole,

2-( l,2,3-thiadiazol-4-ylcarbonylamino)-imidazole,

and

' 2- 1 ,2,5-thiadiazol-3-ylcarbonylamino)-imidazole,

EXAMPLE 2 A solution of 5 g. of 2- phenylcarbonylaminoimidazole [(Ill),R phenyl] and 6 g. of phosphorous pentasulfide in 200 ml. of pyridine isheated in an oil bath at lOO-l lOC. for eighteen hours. The bulk of thepyridine is removed under vacuum and the residue is treated with 500 ml.of saturated potassium bicarbonate solution, filtered and recrystallizedfrom methanol to yield 2- phenylthiocarbonylaminoimidazole (IV), Rphenyl Similarly, substituting a stoichiometric equivalent amount of theother compounds obtained in Example 1A (or Example 18) for 2-phenylcarbonylaminoimidazole, and following the procedure of Example 2is productive of 2-(4-chlorophenylthiocarbonylamino)-imidazole,

2-( 4-methoxyphenylthiocarbonylamino)-imidazole,

2-( 4-methylphenylthiocarbonylamino )-imidazole,

2-( 4-methylthiophenylthiocarbonylamino imidazole,

2-( 4-methylsulfinylphenylthiocarbonylamino imidazole,

2-( 4-tert.-butylphenylthiocarbonylamino )-imidazole,

2-(4-trifluoromethylphenylthiocarbonylamino)- imidazole,

2-(2-furylthiocarbonylamino )-imidazole,

2-( 3 -furylthiocarbonylamino )-imidazole,

2-( Z-naphthylthiocarbonylamino)-imidazole,

2-( 2-thienylthiocarbonylamino )-imidazole 2-(3-thienylthiocarbonylamino )-imidazole 2-( 2-thiazolylthiocarbonylamino)-imidazole,

2-(4-thiazolylthiocarbonylamino)-imidazole,

2-( 5 -thiazolylthiocarbonylamino )-imidazole,

2-(2-methyl-4-thiazolylthiocarbonylamino)- imidazole,

2-( 2-pyridylthiocarbonylamino)-imidazole,

2-( 3-pyridylthiocarbonylamino)-imidazole, and

2-(4-pyridylthiocarbonylamino)-imidazole,

2-( 2-pyrazinylthiocarbonylamino )-imidazole,

2-( 3 -isothiazolylthiocarbonylamino )-imidazole2-(4-isothiazolylthiocarbonylamino)-imidazole, and

2-( 5-isothiazolylthiocarbonylamino )-imidazole,

2-( l,2,B-thiadiazol-4-ylthiocarbonylamin0 imidazole, and

2-( 1 ,2,5-thiadiazol-3-ylthiocarbonylamino imidazole, respectively.

EXAMPLE 3 A. To 0.21 g. of 2-(4-thiazolylthiocarbonylamino)- imidazole[(IV), R 4-thiazolyl], dissolved in 10 ml. of chloroform at 20-25C.(room temperature), there is added dropwise 0.09 ml. of sulfurylchloride in 5 ml.

of chloroform. After 2 hours, the reaction mixture is with 50 ml. ofchloroform and 50 ml. of aqueous am- -"trrcixiiaihThe chloroform layeris separated, dried'over magnesium sulfate,'and' concentrated.The'product is recrystallized from methanol to yield 2-(4-thiazolyl)- jl ,2, '4- thiadiaz'olo-[2,3-a]-imidazole [(I), R I thiaz olyl].

Similarly, substituting a stoichiometric equivalent amount of othercompounds obtained in Example 2,

2-phenylthiocarbonylaminoimidazole,

" 2 4-chlorophenylthiocarbonylamino)-imidazole,

2-(4-methoxyphenylthiocarbonylamino)-imidazole, 2-(4-methylphenylthiocarbonylamino )-imidazole,2-(4-methylthiophenylthiocarbonylamino)- imidazole,

2-(4-methylsu finylthiocarbonylamino)-irnidazole,

2 -(4-tert.-butylphenylthiocarbonylamino)-imidazole, 2-(4-trifluoromethylphenylthiocarbonylamino)- imidazole,

2'-( 2 furylthiocarbonylamino )-imidazole,

' 2-(3-furylthiocarbonylamino)-imidazole,

2-( 2-naphthylthiocarbonylamino )-imida2ole,2-(2-thienylthiocarbonylamino)-imidazole, 2-(3-thienylthiocarbonylamino)-imidazole, 2-('2thiazolylthiocarbonylamino)-imidazole, 2-( 5-thiazolylthiocarbonylamino)-imidazole, '2-( 2-methyl-4-thiazolylthiocarbonylamino)- imidazole, t

2-( 2 -pyridylthioca rbonylamino )-imidazole,

, 2 3-pyridylthiocarbonylamino )-imidazole,

' 2-(4-pyridylthiocarbonylamino)-imidazole,

2-( 2-pyraz'in ylthiocarbonylamino )-imidazole,

' 2-( 3-isothiazolylthiocarbonylamino )-imidazole,2-(4-isothiazolylthiocarbonylamino)-imidazole, 2-(5isothiazolylthiocarbonylamino )-imidazole, 2-(l,2,3-thiadiazol-4-ylthiocarbonylamino)- imidazole, 2-(l,2,5-thiadiazol-3-ylthiocarbonylamino)- imidazole, for 2-(4-thiazolyl)thiocarbonylaminoimidazole' in the procedure'of Example 3 is productiveof 2-phenyll ,2,4-thiadiazolo-[ 2,3-a]-imidazole, 2-(4-chlorophenyl)-1,2,4-thiadiazolo-[2,3-a]- imidazole, 2-(4-methoxyphenyl )-l,2,4-thiadiazolo-[ 2,3-a1- imidazole, 2-(4-methylphenyl)- l,2,4-thiadiazolo-[2,3-a]

imidazole, 2-(4-methylthiophenyl)-l ,2,4-thiadiazolo-[ 2,3-a]-imidazole, 2-('4-methylsu finylphenyl)- l ,2,4-thiadiazolo-[ 2,3-a]-imidazole, 2-( 4-tert.-butylphenyl l ,2,4-thiadiazolo-[ 2,3-a]-imidazole,

2- 4-trifluoromethylphenyl)- 1 ,2,4-thiadiazolo-[2,3-

a]-imidazole, i

2-( 2-furyl)- l ,2,4 -thiadiazolo-[2,3-a]-imidazole,

2-( 3-furyl l ,2,4-thiadiazolo-[ 2,3-a]-imidazole,

2-( Z-naphthyl l ,2,4-thiadiazolo-[ 2,3-a]-imi'dazole,

2-( 2-thienyl )-l ,2,4-thiadiazolo-[2,3-a]-imidazole,

2-( 3-thienyl l ,2,4-thiadiazolo-[2,3-a]-imidazole,

2-( 2-thiazolyl )-l ,2,4-thiadiazolo-[ 2,3-al-imidazole,

2-( 5 thiazolyl I ,2,4-thiadiazolo-[ 2,3-a]-imidazole,

2-( 2-methyl-4-thiazolyl )-l ,2,4-thiadiazolo-[ 2,3-a1- imidazole, x

2-(2-pyridyl)- l ,2,4-thiadiazolo-[2,3-a1-imidazole, 2-( S-pyridyl l,2,4-thi adiazo lo-[2,3-a]-imidazole, 2-(4-pyridyl l ,2,4-thiadiazolo-2,3-a -imidazole, 2-( 2-pyrazinyl )-.l ,2 -,4thiadiazolo-[ 2,3 -a-imidazolc, 2-,(3fisothiazolyl)5l',2,4gthiadiazolo [2,3 -a

imidazole,

imidazole,respectively. i v

B. To a solution of 0.4 g. br 2- phenylthiocarbonylaminoiniidazole[(lV), R phenyl] in 20 ml. of chloroform there "is added dropwise, at20-2sc., a solutionof 0.165 m1'.; of sulfuryl chloride in 5 ml. ofchloroform.' iAfter 2 hours 'tlie' preeipitate which forms is filtered,dissolved in methanol, andprecipitated from ether to yield2-phe'n'yl-l;2,4- thiadiazolo-[2,3-a1-imidazole hydrochloride.

C. To a solution of 0.19 g. of 2-(2-furylthiocarbonylamino)-imidazole[(IV), R 2-furyl]-in"25 ml. of chloroform, at 2025C, there is addeddropwise 0.09 ml. of sulfuryl chloride in 5 ml. of chloroform. After 4hours, the reaction mixture is chilled in ice, followed by filtration toyield 2-( 2-furyl)-l,2,4 thiadiazolo-[ 2,3-a]- imidazole hydrochloride.M f 4 D. To 0.2 g. of 2-(3-furyltliiocarboriylamino)- imidazole [(IV), R3-furyl] in lOiml. of chloroform, at 2025C, there is added dropwise O.'lml. of sulfuryl chloride in 2 ml. of chloroforrrifAfter IOminutes thereaction mixture is concentra t eidigat .lO 20 ,C. under vacuum to givea residue which is' treatefd with methanol and filtered. Theresidueobtairied following filtration is treated with dilute aqueousammonia to give a precipitate which is filtered dried to yield 2-(3-furyl)- l.,2,4-thiadiazolo-[ 2,3-aI-imidazole.

In the examples above, specific reaction sequences have been extended,.in a general sense, to the'preparation of other similar and relatedcompounds; It should be understood, however, that with respect to any'compound which hasbeen prepared by the extension of a specific reactionsequence, it maybe necessary or desirable to utilize solvents, reactionmedia, recrystallization. media reaction times or temperaturesfetc otherthan theones given in the specific reaction sequence upon which suchextension is based. Additionally, the specific reaction sequence ormanner in which particular compounds are to be prepared will depend,inter alia, upon the, availability ofthe necessary'starting material, orthe ease in which the desired starting materials can be prepared, andthe reactivity thereof. These variations aredeemed to be within theskill of those working in this art and will be apparentfroin-aconsideration of the particular reactants utilized and/or particularcompound'desired to be produced.

While theprese'ntinventi'on has been described with reference tospecific embodimentsthe'reof, it should be understood by those skilledin this art that various changed may be-mafd eland'equivalents may besubstituted without departing fromv the true spirit and scope of theinvention. Irr addition, many modifications may be made to adapt; a"particularsituation: material or compositio'njof matter,procesgiprocessstepor steps,

or then-present objective to the spirit of this invention withoutdeparting from its essential teachings.

What is claimed is:

1. A compound represented by the formula:

wherein R is in which R, and R are each hydrogen, lower alkoxy,

halo, nitro, lower alkyl, lower alkylthio, lower alkylsulfinyl, ortrifluoromethyl; I

R;, is hydrogen, lower alkoxy, halo, nitro, or lower alkyl; and thepharmaceutically acceptable salts thereof.

2. A compound of claim 1 wherein R is phenyl, 4- chlorophenyl,4-methoxyphenyl, 4-methylpheny, 4- methylthiophenyl,4-methylsulfinylphenyl, 4-tert.- butylphenyl, 4-trifluoromethylphenyl,2-furyl, 3-furyl, 2-naphthyl, Z-thienyl, and 3-thienyl.

3. The compound of claim 2 wherein R is phenyl, 2- phenyl- 1,2,4-thiadiazolo-[2,3-a]-imidazole.

4. The compound of claim 2 wherein R is 4- chlorophenyl, 2-(4-chlorophenyl )-l ,2,4-thiadiazolo- [2,3-a] -imidazole.

5. The compound of claim 2 wherein R is 4- methoxyphenyl,2-(4-methoxyphenyl)-1,2,4- thiadiazolo-[ 2,3-a] -imidazole.

6. The compound of claim 2 wherein R is 4- methylphenyl, 2-(4-methylphenyl )-l ,2,4-thiadiazolo- [2,3-a1-imidazole.

7. The compound of claim 2 wherein R is 4- methylthiophenyl, 2-(4-methy1thiophenyl )-l ,2,4- thiadiazolo-[ 2,3-a] -imidazole.

8. The compound of claim 2 wherein R is 4-methylsulfinylphenyl, 2-(4-methylsulfinylphenyl 1 ,2,4- thiadiazolo-[2,3-a1-imidazole.

9. The compound of claim 2 wherein R is 4-tert.- butylphenyl,2-(4-tert.-butylphenyl l ,2,4-thiadiazolo- [2,3-a]-imidazole.

10. The compound of claim 2 wherein R is 4-trifluoromethylphenyl-2-(4-trifluoromethylphenyl)- l,2,4-thiadiazolo-[2,3-a1-imidazole.

11. The compound of claim 2 wherein R is 2-furyl, 2-( 2-furyl l,2,4-thiadiazolo-[2,3-a]-irnidazole.

12. The compound of claim 2 wherein R is 3-furyl, 2-( 3-furyl l,2,4-thiadiazolo-[2,3-a1-iniidazole.

13. The compound of claim 2 wherein R is 2- naphthyl, 2-( Z-naphthyl 1,2,4-thiadiazolo-[ 2,3-a]- imidazole.

14. The compound of claim 2 wherein R is 2-thienyl,

2-(2-thienyl)-1,2,4-thiadiazolo[2,3-a]-imidazole.

15. The compound of claim 2 wherein R is 3-thienyl, 2-( 3-thienyl l,2,4-thiadiazolo-[ 2,3-a]-imidazole.

1. A COMPOUND REPRESENTED BY THE FORMULA:
 2. A compound of claim 1wherein R is phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylpheny,4-methylthiophenyl, 4-methylsulfinylphenyl, 4-tert.-butylphenyl,4-trifluoromethylphenyl, 2-furyl, 3-furyl, 2-naphthyl, 2-thienyl, and3-thienyl.
 3. The compound of claim 2 wherein R is phenyl,2-phenyl-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 4. The compound of claim 2wherein R is 4-chlorophenyl,2-(4-chlorophenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 5. The compoundof claim 2 wherein R is 4-methoxyphenyl,2-(4-methoxyphenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 6. The compoundof claim 2 wherein R is 4-methylphenyl,2-(4-methylphenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 7. The compoundof claim 2 wherein R is 4-methylthiophenyl,2-(4-methylthiophenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 8. Thecompound of claim 2 wherein R is 4-methylsulfinylphenyl,2-(4-methylsulfinylphenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 9. Thecompound of claim 2 wherein R is 4-tert.-butylphenyl,2-(4-tert.-butylphenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 10. Thecompound of claim 2 wherein R is4-trifluoromethylphenyl-2-(4-trifluoromethylphenyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 11. The compound of claim 2 wherein R is 2-furyl,2-(2-furyl)-1, 2,4-thiadiazolo-(2,3-a)-imidazole.
 12. The compound ofclaim 2 wherein R is 3-furyl, 2-(3-furyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 13. The compound of claim 2 wherein Ris 2-naphthyl, 2-(2-naphthyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole. 14.The compound of claim 2 wherein R is 2-thienyl,2-(2-thienyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.
 15. The compound ofclaim 2 wherein R is 3-thienyl,2-(3-thienyl)-1,2,4-thiadiazolo-(2,3-a)-imidazole.